1. Field of the Invention
This invention relates generally to non-insulin dependent diabetes mellitus (NIDDM) (type II) and obesity, and specifically to a novel Trp64Arg mutation in the .beta.3-adrenergic receptor that increases susceptibility to obesity and type II diabetes.
2. Description of Related Art
Non-insulin dependent diabetes mellitus (NIDDM) is one of the most common inherited diseases in man with an estimated prevalence in Caucasian populations of 8-10% (Harris, et al., Diabetes, 36:523-534, 1987). Although most forms of NIDDM do not exhibit simple Mendelian inheritance, the contribution of heredity is well recognized (Rotter, et al., Diabetes Mellitus: Theory and Practice, 378-413, 1990). The genetic basis of a few rare monogenic syndromes of NIDDM have been elucidated, but together, these syndromes account for a very small minority of cases (Taylor, et al., Endocrine Rev., 13:566-595, 1992; Froguel, et al., N. Engl. J. Med., 328:697-702, 1993; Steiner, et al., Diabetes Care, 13:600-609, 1990; and Kadowaki, et al., N. Engl. J. Med., 330:962-968, 1994). It is likely that the common forms of NIDDM are complex and heterogenous, and result when a pool of mutant genes, each of which contributes modestly and in a subtle way, interact with each other and with environmental, aging and behavioral influences to lead to the expression of the disease. This pool of genes may vary between populations and among individuals within a population, despite the illusion of a clinically homogenous phenotype.
Obesity is a known risk factor for the development of NIDDM (Barrett-Conner, E., Epidemiol. Rev., 11:172-181, 1989; and Knowler, et al., Am. J. Clin. Nutr., 53:1543-1551, 1991), and although less well studied than NIDDM, also has clear genetic determinants (Bouchard, C., World Rev. Nutr. Diet, 72:68-77, 1993; and Stunkard, et al., N. Engl. J. Med., 314:193-197,1986). Potential candidate genes for obesity (and therefore also NIDDM) include those that influence energy expenditure. In adult Pima Indians, resting metabolic rate (RMR) is familial (Bogardus, et al., N. Engl. J Med, 315:96-100, 1986 ), and in prospective studies, a low RMR is a risk factor for weight gain and obesity (Ravussin, et al., N. Engl. J Med, 318:467-472, 1988). Studies in other populations (Bouchard, et al., Metabolism, 38:364-370, 1989; and Griffith, et al., Lancet, 336:76-78, 1990), as well as in animal models (Coleman, D. L., Diabetes, 31:1-6, 1992), support the relationship between heredity, low RMR and obesity. In rodents, RMR is regulated by the sympathetic nervous system and acts through modulation of thermogenesis in brown adipose tissue (Lowell, et al., Nature, 366:740-749, 1993). Although humans do not have anatomically distinct deposits of brown adipose tissue, the identification of human uncoupling protein, a molecular marker widely regarded as being specific for brown adipose tissue, suggests that modulation of thermogenesis in adipose tissue may also be important in humans (Cassard, et al., J. Cell Biochem., 43:255-264, 1990).
Obesity represents a primary health concern amongst industrialized countries. Studies on twins, adopted children and on animal models of obesity have shown that genetic factors are implicated in the dynamics of gaining weight (Bouchard, C., Perusse, L., Ann. Rev. Nutr., 8:259-277, 1988). Morbid obesity in humans appears to have a particularly strong genetic component (Price, et al., Hum. Biol., 62:, 1990; and Adams, et al., Obes. Res., 1:261-270, 1993). However, the molecular basis of inheritance of obesity in humans is unknown. Obesity results from an imbalance between caloric intake and energy expenditure. As adipose tissue plays a crucial role in the regulation of energy storage and mobilization, it has been the focus for studies involved in the identification of candidate genes. Recently, positional cloning approaches have succeeded in identifying an obesity gene in a monogenic rodent model, the ob mouse (Zhang, et al., Nature, 372:425-432, 1994). The human ob homologue has been cloned, but mutations, deletions, or polymorphisms in this gene have yet to be identified. In humans, evidence supports the involvement of several genes as well as environmental and behavioral influences in the predisposition, onset and progression of obesity and NIDDM.
The recent localization of the .beta..sub.3 -adrenergic receptor (.beta.3AR) in adipose tissue (Emorine, et al., Science, 245:1118-1121, 1989; Spronsen, et al., Eur. J. Biochem., 213:1117-1124, 1993; and Krief, et al., J. Clin. Invest., 91:344-349, 1993) has spurred great interest in its potential role in the regulation of energy expenditure. Evidence in support of a role for the .beta.3AR in the development of obesity and NIDDM include: i) .beta.3AR expression is markedly decreased in rodent models of obesity (Collins, et al., Mol. Endocrinol., 8:518-527, 1994; and Muzzin, et al., J. Biol Chem., 266:24053-24058, 1991); ii) .beta.3AR gene knock-out mice have a marked reduction in .beta.-agonist stimulated lipolysis; iii) insulin downregulates .crclbar.3AR expression in vitro with a concomitant decrease in lipolysis and increase in lipogenesis (Feve, et al., Proc. Natl. Acad. Sci, 91:5677-5681, 1994); and iv) .beta..sub.3 -specific agonists have potent antiobesity and antidiabetic effects in both animals (Hims-Hagen, et al., Am. J. Physiol, 266:R1371-1382, 1994; and Connacher, et al., Am. J. Clin. Nutr., 55:258S-261S, 1992) and humans (Mitchell, et al., Int. J. Obes., 13:757-766, 1989).
There is a need to identify genes and defects in those genes that are directly related to obesity and diabetes. Such genes are useful as molecular markers for the early detection of susceptible individuals so that intervention regimes may be instituted for delay or prevention of obesity/diabetes disorders. A delay in the onset of diabetes would markedly reduce morbidity and mortality due to chronic complications. Further, identification of specific susceptibility genes would allow for the design of more effective medications having specific molecular targets.